Glucagon is a 29 amino acid hormone processed from its proform in the pancreatic alpha cells by cell specific expression of prohormone convertase 2 (Furuta et al., J. Biol. Chem. 276: 27197-27202 (2001)). During fasting, glucagon secretion increases in response to falling glucose levels. Increased glucagon secretion stimulates glucose production by promoting hepatic glycogenolysis and gluconeogenesis. Thus glucagon counterbalances the effects of insulin in maintaining normal levels of glucose in animals.
The glucagon receptor (GCGR) is a member of the secretin subfamily (family B) of G-protein-coupled receptors (GCGR). The glucagon receptor is predominantly expressed in the liver, where it regulates hepatic glucose output, and the kidney, reflecting its role in gluconeogenesis. The activation of the glucagon receptors in the liver stimulates the activity of adenyl cyclase and phosphoinositol turnover which subsequently results in increased expression of gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase (FBPase-1), and glucose-6-phosphatase (G-6-Pase). In addition, glucagon signalling activates glycogen phosphorylase and inhibits glycogen synthase.
Studies have shown that higher basal glucagon levels and lack of suppression of postprandial glucagon secretion contribute to diabetic conditions in humans (Muller et al., N Eng J Med 283: 109-115 (1970)). Targeting glucagon production or function may be one method of controlling and lowering blood glucose. There is a continuing need to provide effective treatments for type 2 diabetes. The present invention addresses this need by providing novel compositions and methods for treating type 2 diabetes and related diseases.